Modifying effects of IL-6 polymorphisms on body size-associated breast cancer risk

Objective: The association between obesity and breast cancer risk is complex. We examined whether the association between body size and breast cancer risk is modified by interleukin-6 (IL6) genotype. Methods and Procedures: Five polymorphisms in the IL- 6 gene (rs1800797/-596A>G, rs1800796/-572G>C, rs1800795/-174G>C, rs2069832/IVS2G>A, and rs2069849 exon 5 C>T) were studied. We investigated IL6 genotypes and haplotypes with indicators of body size among non-Hispanic white (NHW) and Hispanic/American Indian (AI) breast cancer cases and controls living in the Southwestern United States. Results: We observed lower mean levels of BMI among NHW women who carried one or two copies of the GGCAC haplotype (in order: rs1800797, rs1800796, rs1800795, rs2069832, and rs2069849; P trend 0.02). This haplotype, with an estimated frequency of 43% in NHW study controls, was considerably less common in Hispanic/AI controls (19%). We did not detect significant interactions between IL6 genotypes or haplotypes and BMI categorized as low/normal (< 25), overweight (25 to < 30), or obese (>= 30) and breast cancer risk in either NHW or Hispanic/AI women. However, we detected consistent and significant interactions between waist-to-hip ratio (WHR) and IL6 rs1800795/-174G>C genotype for breast cancer risk. These associations were restricted to postmenopausal NHW women. Among women without recent hormone exposure, those with a WHR > 0.9 and the rs1800795 GG genotype had a greater than threefold increased risk of breast cancer (odds ratios (ORs) 3.22, 95% confidence intervals (CIs) 1.27, 817) when compared with women with a WHR < 0.8 and the rs1800795 GG genotype (P interaction 0.01). Discussion: These data suggest that IL- 6 genotypes may influence breast cancer risk in conjunction with central adiposity.